This invention relates to vitamin D compounds useful in treating and/or preventing primary hyperparathyroidism and/or the symptoms thereof, and more particularly to the use of the vitamin D compound 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D3, otherwise referred to herein as “2MD,” to treat primary hyperparathyroidism and/or to treat and/or prevent the symptoms thereof.
“Hyperparathyroidism” refers to a disorder of the parathyroid glands in which the parathyroid glands exhibit overactivity. “Primary” hyperparathyroidism means the disorder originates in the parathyroid glands themselves in contrast to “secondary” hyperparathyroidism which means the disorder results subsequent to another underlying disease or disorder such as renal failure.
In primary hyperparathyroidism, the parathyroid glands become overactive and release excessive parathyroid hormone (PTH) into the blood stream. One of the primary functions of PTH is to increase serum calcium levels. When the parathyroid glands sense a low level of calcium in blood serum via calcium receptors (CaRs) present in the parathyroid glands, the parathyroid glands are stimulated to secrete PTH into the blood stream. The PTH secreted into the blood stream causes mobilization of calcium from bones and increased absorption of calcium by the small intestine, both of which result in increasing serum calcium levels. As such, serum PTH levels and serum calcium levels are controlled by a negative feedback mechanism.
Because PTH results in increasing, serum calcium levels, excessive serum PTH results in excessive serum calcium levels or “hypercalceinia,” which presents a number of health risks. Hypercalcemia may cause the kidneys to excrete more calcium in the urine, which can lead to kidney stones. Hypercalcemia also might contribute to other problems, such as heart disease, high blood pressure, and difficulty with concentration. Indirect symptoms of mildly elevated serum calcium levels may include joint aches, fatigue, weakness, loss of appetite, mild depression, and difficulty concentrating. In addition to causing hypercalcemia, excessive PTH also may result in weakened hones due to excessive mobilization of calcium from bones.
About 100,000 people in the United State develop primary hyperparathyroidism each year. The disorder is diagnosed most often in people between age 50 and 60, and women are affected more often than men. In particular, primary hyperparathyroidism may be observed in women that have been diagnosed with a bone metabolic disorder such as osteopenia or osteoporosis. In the majority of patient with primary hyperparathyroidism, a benign tumor called an adenoma has formed in the parathyroid glands which causes the glands to become overactive. Less frequently, primary hyperparathyroidism is caused by a malignant tumor or cancer of the parathyroid gland. Parathyroid glands also may become overactive because of lithium therapy, past radiation to the neck, or certain gene defects.
The majority of people with hyperparathyroidism have few or no symptoms. In these people, hyperparathyroidism is typically detected when a blood test is done for some other reason and abnormally high serum calcium levels are observed, which may be due to excessive serum PTH levels. Most often, the serum calcium levels are only mildly elevated or are elevated intermittently. Symptoms become more noticeable as the parathyroid hormone (PTH) and serum calcium levels rise to more severe levels. At higher levels of PTH and serum calcium, there may be a significant loss of appetite, nausea, constipation, excessive thirst, or frequent urination. In addition severely high calcium levels may result in impaired kidney function, kidney stones, bone disease, and rheumatologic symptoms.
In patients exhibiting severely high serum calcium levels due to primary hyperparathyroidism, the most common form of treatment is surgery to remove the overactive parathyroid glands. Non-surgical treatment methods may include modulating calcium intake and supplementing vitamin D intake. Vitamin D deficiency can stimulate PTH secretion and bone resorption, so adequate vitamin D levels are beneficial. In order to treat bone loss, for example osteopenia or osteoporosis, bisphosphonates may be administered.
In order to reduce PTH secretion directly, a calcimimetic also may be administered to treat primary hyperparathyroidism. A calcimimetic is an agent that mimics the effect of calcium on the calcium receptors (CaRs) in the parathyroid gland. As such, calcimimetics increase the sensitivity of the calcium-sensing receptor (CaR) to circulating serum calcium reducing the secretion of PTH and the serum calcium concentration. Calcimimetics include the compound named (R)—N-[1-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]propan-1-amine otherwise referred to as “cinacalcet.”
Vitamin D analogs have been approved by the US Food and Drug Administration (FDA) for treating secondary hyper parathyroidism, such as secondary hyperparathyroidism subsequent to renal failure. The kidneys are important for regulating PTH secretion and serum calcium levels because vitamin D is metabolized in the kidneys into its active form which is called “calcitriol.” One of the functions of calcitriol is to mobilize calcium from bone and to increase absorption of calcium by the small intestine in order to increase serum calcium levels. Calcitriol and other active vitamin D analogs also decrease the expression and secretion of PTH from the parathyroid glands. (See Slatopolsky et al., Am. J. Kidney Dis. Vol. 26, No. 5, 1995: pp 852-860.) In a patient with renal failure, the kidneys no longer metabolize vitamin D to produce calcitriol, and as a result, the patient no longer has the ability to increase serum calcium levels via the effect of calcitriol. Likewise, the patient no longer has the ability to regulate the expression and secretion of PTH from the parathyroid glands via the effect of calcitriol. When calcitriol and serum calcium levels are low in patients with renal failure, the parathyroid gland secretes excess PTH in order to increase serum calcium levels via mobilizing calcium from bone and increasing absorption of calcium by the small intestine. Because vitamin D analogs have been shown to act on the parathyroid glands and decrease secretion of PTH, vitamin D analogs have been approved by the FDA for treating secondary hyperparathyroidism, including, paraealcitol, which is sold under the trademark Zemplar®. (See also U.S. Published Application No. 2114/0005152, the content of which is incorporated herein by reference in its entirety).
However, no vitamin D analogs have been approved for treating primary hyperparathyroidism. Thus, new vitamin D analogs that can be used to treat primary hyperparathyroidism are highly desirable, including vitamin D analogs that can be administered to reduce PTH secretion. Here, a highly potent active vitamin D analog (AVD), namely, 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D3, otherwise referred to as “2MD” is shown to suppress PTH production in patients having primary hyperparathyroidism without increasing serum calcium or serum phosphate. As such, 2MD is useful for treating primary hyperparathyroidism in patients without increasing serum calcium or serum phosphate.